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Targeting the SWI/SNF Chromatin Remodeling Complex Subunit SMARCA4 in ALL (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2555; Furthermore, we demonstrate a direct correlation between high SMARCA4 expression and poor patient outcomes, as well as a clear dependency of Ph-like B-ALL on SMARCA4. Based on our data, applying a SMARCA4 inhibitor-based therapy may specifically benefit patients with Ph-like B-ALL.
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Journal, BRCA Biomarker, PARP Biomarker: SMARCA2 and SMARCA4 Participate in DNA Damage Repair. (Pubmed Central) - Jul 31, 2024 The rash was follicular based and exhibited some clinical features of KP eruptions seen with BRAF inhibitors (up to 40%) and combination BRAF/MEK inhibition (3-10%) . This study reveals SMARCA2/4 as a DNA damage repair factor for double-strand break repair.
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Enrollment change, Trial completion date, Trial termination, Trial primary completion date, Metastases: FHD-286 in Subjects With Metastatic Uveal Melanoma (clinicaltrials.gov) - Apr 25, 2024 P1, N=76, Terminated, Conclusions : In summary we provide evidence for a critical role of SMARCA4 as a key regulator of the NE phenotype, as well as a potential therapeutic target for the treatment of SCLC. N=125 --> 76 | Trial completion date: Aug 2025 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2023 --> Nov 2023; Sponsor terminated the study for business reasons.
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Preclinical efficacy of BRG1/BRM ATPase inhibitor in B lymphoblastic leukemia. (Hall A; Poster Bd #: 397) - Apr 24, 2024 - Abstract #ASCO2024ASCO_3400; P1 In vivo validation is ongoing. Further directions include defining the effect of FHD-286 on chromatin remodeling, gene expression, and exploring efficacy in combination therapy, which has been shown to increase FHD-286 efficacy against AML.
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Shifted mSWI/SNF complex assembly and function underlie therapeutically targetable dependencies in endometrial carcinoma (Ballroom 6 A - Upper Level - Convention Center) - Mar 5, 2024 - Abstract #AACR2024AACR_3370; Further, FHD-286 synergized with carboplatin, leading to significant reduction in tumor burden in ARID1A- and ARID1A/B-mutant PDX models. Taken together, these findings reveal the oncogenic contributions of shifted of mSWI/SNF family complex abundance and chromatin-level gene regulatory function and suggest therapeutic utility of mSWI/SNF complex small molecule inhibitors in endometrial carcinoma and other cBAF-disrupted cancer types.
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Novel combination therapies to overcome non-genetic/adaptive menin inhibitor resistance in AML with MLL1r or mtNPM1 (Ballroom 6 B - Upper Level - Convention Center) - Mar 5, 2024 - Abstract #AACR2024AACR_3342; In vivo treatment with FHD-286 and OTX015 or SNDX-5613 significantly reduced the AML burden in mice bearing OCI-AML3-MITR xenografts. These findings underscore preclinical activity of epigenetically-targeted agent-based combinations and highlight their promise in overcoming MI resistance in AML with MLL1r or mtNPM1.
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Enrollment open, Enrollment change, Trial completion date, Trial primary completion date, Combination therapy, Monotherapy, Metastases: FHD-286-C-002: FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies (clinicaltrials.gov) - Aug 24, 2023 P1, N=144, Recruiting, These findings demonstrate the pre-clinical efficacy of FHD-286-based rational combinations and underscore their promise against AML with MLL1r or mtNPM1. Active, not recruiting --> Recruiting | N=50 --> 144 | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Sep 2023 --> Sep 2025
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Enrollment closed, Metastases: FHD-286 in Subjects With Metastatic Uveal Melanoma (clinicaltrials.gov) - Aug 24, 2023 P1, N=125, Active, not recruiting, Active, not recruiting --> Recruiting | N=50 --> 144 | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Sep 2023 --> Sep 2025 Recruiting --> Active, not recruiting
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Enrollment closed, Combination therapy, Monotherapy, Metastases: FHD-286-C-002: FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies (clinicaltrials.gov) - Jun 27, 2023 P1, N=50, Active, not recruiting, Updated dosing, safety, tolerability, PK and anti-tumor activity data will be shared at the meeting. Suspended --> Active, not recruiting
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The dual BRM/BRG1 (SMARCA2/4) inhibitor FHD-286 induces differentiation in preclinical models of AML (Section 38; Poster Board #25) - Mar 14, 2023 - Abstract #AACR2023AACR_3534; Elaboration of this in both CDX and PDX in vivo models also shows significant survival benefit in difficult to treat mutational backgrounds. Taken together, these findings suggest that FHD-286 is able to target blast progenitor populations that are heavily BRM/BRG1-dependent, and that combination with standard of care agents can achieve profound, mutationally agnostic antitumor activity in AML.
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Pre-clinical efficacy of targeting BAF complexes through inhibition of the dual ATPases BRG1 and BRM by FHD-286 in cellular models of AML (Room W224 - Convention Center) - Mar 14, 2023 - Abstract #AACR2023AACR_3156; Additionally, co-treatment with FHD-286 and venetoclax, decitabine or OTX015, as compared to each drug alone or vehicle control, significantly reduced AML burden and improved the overall survival of the NSG mice, without inducing significant toxicity. Taken together, these findings highlight the promise of FHD-286 treatment alone and in rational combinations in exerting significant anti-AML efficacy against cellular models of AML, especially those with MLL-r, mtNPM1 or chromosome 3q26 lesions and EVI1 overexpression.
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Synergistic efficacy of the BRM/BRG1 ATPase inhibitor, FHD-286, and anti-PD-1 antibody in mouse syngeneic tumor models (Hall C) - Oct 6, 2022 - Abstract #SITC2022SITC_1200; P1 FHD-286 increased MHCI expression on B16F10 cells, and increases in IFNγ and Th1-type chemokine CXCL10 levels were observed in immunocompetent mice following treatment, suggesting that combinatorial activity may result from effects on both the tumor and the immune system. Conclusions FHD-286 has the potential to sensitize tumor to immune-checkpoint inhibition and represents a novel combination approach for cancer immunotherapy.
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Trial completion date, Trial suspension, Trial primary completion date, Combination therapy, Monotherapy, Metastases: FHD-286-C-002: FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies (clinicaltrials.gov) - Sep 8, 2022 P1, N=50, Suspended, Conclusions FHD-286 has the potential to sensitize tumor to immune-checkpoint inhibition and represents a novel combination approach for cancer immunotherapy. Trial completion date: Jun 2024 --> Jun 2025 | Active, not recruiting --> Suspended | Trial primary completion date: Sep 2022 --> Sep 2023
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Enrollment closed, Trial primary completion date, Combination therapy, Monotherapy, Metastases: FHD-286-C-002: FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies (clinicaltrials.gov) - May 23, 2022 P1, N=50, Active, not recruiting, Trial completion date: Jun 2024 --> Jun 2025 | Active, not recruiting --> Suspended | Trial primary completion date: Sep 2022 --> Sep 2023 Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2022 --> Sep 2022
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